2,6-diamino-1,4-dihydropyridine derivatives

ABSTRACT

2,6-Diamino-1,4-dihydropyridines bearing carbonyl functions in the 3- and 5-positions and being substituted in the 4-position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group are antihypertensive agents and coronary vessel dilators. The compounds, of which 2,6-diamino-4-(3-nitrophenyl)-1,4dihydropyridine-3,5-dicarboxylic acid 3,5-diethyl ester is a representative embodiment, are prepared through condensation of an amidine with either an aldehyde or an ylidenecyanoacetoacetic acid ester.

United States Patent [191 Meyer et al.

[ Dec. 17, 1974 2, 6-DIAMINO-l, 4-DIHYDROPYRIDINE DERIVATIVES [73]Assignee: Bayer Aktiengesellschaft,

Leverkusen, Germany [22] Filed: Feb. 28, 1973 [21] Appl. No.2 336,483

[30] Foreign Application Priority Data Mar. 6, l972 Germany 2210687 [52]US. Cl 260/2948 G, 260/2564 R, 260/2565 R, 260/283 S, 260/283 CN,

260/2955 R, 260/2955 B, 260/2948 F,

[51] Int. Cl C07d 31/50 [58] Field of Search 260/2948 R, 294.8 F, 294.8G, 260/2955 A. 295. 5 R

Primary Examiner-Alan L. Rotman [57] ABSTRACT2,6-Diamino-l,4-dihydropyridienes bearing carbonyl functions in the 3-and 5-positions and being substituted in the 4-position by lower alkyl,phenyl, substituted phenyl or a heterocyclic group are antihypertensiveagents and coronary vessel dilators. The compounds, of which2,6-diamino-4-(3-nitrophenyl)-l,4- dihydropyridine-3,S-dicarboxylic acid3,5-diethyl ester is arepresentative embodiment, are prepared throughcondensation of an amidine with either an aldehyde or anylidenecyanoacetoacetic acid ester.

22 Claims, N0 Drawings 2,6.-DIAMINO-1,4-DIHYDROPYRIDINE DERIVATIVESDETAILED DESCRIPTION wherein R is hydrogen; lower alkyl; lower alkenyl;lower alkynyl, phenyl; substituted phenyl in which the substituents areone to three members selected from the group consisting of lower alkyl,lower alkoxy, halogeno, nitro, cyano, trifluoromethyl, azido,carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl, loweralkylthio or phenyl; naphthyl; or a heterocyclic ring selected from thegroup consisting of quinolyl, isoquinolyl, pyridyl, pyrimidyl thenyl,furyl and pyrryl, said heterocyclic ring being unsubstituted orsubstituted by one or two members selected from the group consisting oflower alkyl, lower alkoxy and halogeno; and

each of R and R taken independently of the other, is lower alkyl, loweralkoxy, lower alkoxy(lower alkoxy), lower alkenyloxy, lower alkynyloxy,amino, lower alkylamino or di(lower alkyl) amino.

The above compounds can be depicted in tautomeric forms, all of whichare fully equivalent and fully em-' braced by the present invention:

For the sake of brevity and convenience, the l,4- dihydro form isemployed herein.

The term lower alkyl denotes a univalent saturated branched or straighthydrocarbon chain containing from 1 to 6.carbon atoms. Representative ofsuch lower alkyl groups are thus methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec. butyl, tert. butyl, pentyl, isopentyl, neopcntyl.tert. pentyl, hexyl. and the like.

The term lower alkenyl denotes a univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalethylenic unsaturation as, for example, vinyl, allyl, isopropenyl,2-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, Z-hexenyl,4-hexenyl, and the like, preferably having 2 to 4 carbon atoms.

The term lower alkynyl denotes a univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalacetylenic unsaturation as, for example, ethynyl, 2-propynyl.4-pentynyl, and the like, preferably having 2 to 4 carbon atoms.

The term lower alkoxy denotes a straight or branched hydrocarbon chainbound to the remainder of the molecule through an ethereal oxygen atomas, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentoxy and hexoxy.

The term lower alkylthio denotes a branched or straight hydrocarbonchain bound to the remainder of the molecule through a divalent sulfuras, for example, methylthio, ethylthio, propylthio, isopropylthiobutylthio, and the like.

The term halogen denotes the substituents fluro, chloro, bromo and iodo.

As indicated, the present invention also pertains to the physiologicallyacceptable non-toxic acid addition salts of these basic compounds. Suchsalts include those derived from organic and inorganic acids such as,without limitation, hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, methane sulphonic acid, acetic acid, tartaric acid,lactic acid, succinic acid, cit ric acid, malic acid, maleic acid,sorbic acid,-aconitic acid, salicylic acid, phthalic acid, embonic acid,enanthic acid, and the like.

According to the present invention, the foregoing compounds are preparedby reacting an amidine of the formula:

wherein R is as herein defined, with either (a) an aldehyde of theformula RCl-IO wherein R is as herein defined, or (b) with anylidenecyanoacetic acid derivative of the formula:

0 CHR Pd-Jil-iS-CN in which R and R are as herein defined in thepresence of an alkali metal alkoxide such as sodium methoxide. Thecondensations proceed smoothly in good yields simply by heating the twocomponents, generally in the presence of an inert organic solvent suchas methanol, ethanol, propanol and similar alkanols, ethers such asdioxane and diethyl ether, glacial acetic acid, pyridine,dimethylformamide, dimethylsulfoxide, acetonitrile, and the like. Thereactions are conducted at temperatures of from 20 to 200C, convenientlyat the boiling point of the solvent, and while elevated pressure may beutilized, normal atmospheric pressure is generally satisfactory. Thereactants are employed in substantially equimolar amounts when theamidine is reacted with the ylidenecyanoacetic acid whereas at least twomolar equivalents of the amidine are employed per molar equivalent ofthe aldehyde reactant, in which case R and R are the same in thedihydropyridine product. The amidine reactant can be employed as thefree base or in the form of a salt such as the hydrohalide salts withthe amidine being liberated from the salt through treatment with a basicagent such as an alkali metal alkoxide.

It is rather surprising that the above described'condensations producethe desired compounds in such good yields and with such high purity.Thus the water formed in the initial condensation of the aldehyde andamidine could be expected to hydrolyze the resultant ylideneamidine withformation of an lyideneamide. Moreover, while it is known that abenzylideneacetoacetic acid ester can be condensed with an aminocrotonic acid ester to yield a 1,4-dihydropyridine (Knoevenagel, Ber.31, 743, 1898), it would be expected from, for example, Silversmith, J.Org. Chem. 27, 4090 (1952) that the addition of the amidine to the 5ylideneamidine or the ylidenecyanoacetic acid would yield thedihydropyrimidine derivative rather than the dihydropyridine derivative.

Many of the aldehydes utilized as one of the reactants are known to theart and the others can either be generl ated in situ as herein describedor prepared according to methods well known to the art, see for exampleOrg. Reactions Vlll, 218 et seq. (1954). Typical of this reactant arethe following compounds:

benzylidenecyanoacetic acid ethyl ester, benzylidenecyanoacetic acidpropargyl ester, benzylidenecyanoacetic acid B-methoxyethyl ester,1-naphthylidenecyanoacetic acid ethyl ester,2-methoxybenzylidenecyanoacetic acid ethyl ester,2-methylbenzylidenecyanoacetic acid ethyl ester,2-nitrobenzylidenecyanoacetic acid isopropyl ester,2-trifluoromethylbenzylidenecyanoacetic acid ethyl ester,2-cyanobenzylidenecyanoacetic acid methyl ester,2-chlorobenzylidenecyanoacetic acid propyl ester,4-methylmercaptobenzylidenecyanoacetic acid ethyl ester,a-pyridylmethylidenecyanoacetic acid ethyl ester,

formaldehyde, l5 and acetaldehyde, 2-furfurylidenecyanoacetic acid ethylester.

propionaldehyde, The amidine reactants are similarly known or can beisobutyraldehyde, readily produced according to known methods, see forcyclopentaldehyde, example McElvain et al., J.A.C.S., 73, 2760 (1951).

cyclohexanaldehyde, Typical of these reactants are the following:

acrolein, amidinoacetic acid methyl ester,

cyclohex-3-enaldehyde, amidinoacetic acid ethyl ester,

benzaldehyde, amidinoacetic acid n-propyl ester,

2-, 3- and 4-methylbenzaldehyde, amidinoacetic acid isopropyl ester,

2-, 3- d 4 h b ld h d amidinoacetic acid cyclohexyl ester,

3,4 and 5-trimethoxybenzaldehyd amidinoacetic acid B-methoxyethyl ester,

2-isopropoxybenzaldehyde, amidinoacetic acid a-ethoxyethyl ester,

2- 3- d 4 hl b ld h d amidinoacetic acid B-ethoxyethyl ester,

2-, 3- d 4-b b ld h d amidinoacetic acid propargyl ester,

2-. 3- and 4-fluorobenzaldehyde, amidlnoacetamide, and

2.4- and 2.o-dichlorobenzaldehyde. amidlno'NN'dlmethylacetamide- 14- d 23 1i h |b 1d h d As noted above, the compounds of the present inven- 1-3. d 4- i b ld h d tion demonstrate the ability to reduce blood pressure16- d 3 5 di i b ld h d and to effect a dilation of the coronaryvessels. They 3- i 6- b can accordingly be used where either or both ofthese 2 m -3- h 6- hl b |d h d effects are desired. Thus uponparenteral, oral or sub- 2.ni[r 4 chlgrobenzaldehyde lingualadministration, the compounds produce a dis- 2 m .4. b tinct and longlasting dilation of the coronary vessels 2 3 and 4 t ifl th lb ld h dwhich is intensified by a simultaneous nitrite-like effect2.CarbethoWbenzaldehWe, 40 of reducing the load on the heart. The effecton heart 3 Carbomethmybenzaldehyde, metabolism is thus one of energysaving. In addition,

4-6arb0butowbenzaldehyde, the compounds lower the blood pressure ofnormotonic 3-nitro-4-carbethoxybenzaldehyde-4-carboxylic acid andhyPenomc animals and can thu be used as antihy' ethy| ester. pertensiveagents. These properties can be conveg and ymwmmmdehyde, mently observedin well known laboratory models.

6 methy1pyridin 2 a1dehyde, Thus for example the coronary vesseldilation effect pyrimidimialdehyde, can be observed by measuring theincrease in oxygen 4,641imethoxypyrimidin 5 a|dehyde, saturation in thecoronary sinus in the narcotized, heart 2 and muanobenmldemde,catheterized dog, as shown in the following table:

2-methylmercaptobenzaldehyde, 5O

4-methylmercaptobenzaldehyde, Lv. Remm to 2-methylsulphonylbenzaldehyde,Dose A 0 normal 0 1- and z a hthald hyd p d (mg/kg) saturation values(hours) S-bromo-l-naphthaldehyde, 5g Q3 26 2 Z-ethoxy-l-naphthaldehyde,ggogrlsenylizi-ilgl-ss 4-methyll -naphthaldehyde, i g' acid qumolm-2-,3-, 4-, 5-, 6-, 7- and 8-aldehyde, 3,5-diethyl esterisoquinolin-l,3,4-aldehyde, 2Miamino44} 02 26 2 furan-2-aldehyde,

thiophen-Z-aldehyde and pyrrol-Z-aldehyde.

The ylidenecyanoacetic acid reactants are similarly known or can bereadily produced according to known methods, see for example Newman etal., J. Org. Chem., 23, 797 (1958). Typical of these reactants are thefollowing benzylidenecyanoacetic acid methyl ester,

nitrocphenyl 1 ,4-

dihy rop ridine- 3,5-dicarboxylic acid diethyl ester Compound Dose(mg/kg) 2,6-diamino-4-( Z-methylphenyl l ,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester2,6-diamino-4-(2-nitrophenyl)-1,4 dihydropyridine-3,S-dicarboxylic acid3,5-diethyl ester 2,6-diamino-4-( Z-methoxyphenyl l ,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester2,6-diamino-4-(2-cyanophenyl)-1,4-dihydro- 0.3 pyradine-3,S-dicarboxylicacid diethyl ester 2,6 iiamino-4-( B-nitrophenyl l,4-dihydropyridine-3.5-dicarboxylic acid diethyl ester ln addition tothe effect on blood pressure and coronary vessels, the compounds alsolower the excitability of the stimulus formation and excitationconduction system within the heart so that an antifibrillation action isobserved at therapeutic doses. The tone of the smooth muscle of thevessels is also greatly reduced. This vascularspasmolytic action can beobserved in the entire vascular system as well as in more or lessisolated and circumscribed vascular regions such as the central nervoussystem. In addition, a strong muscularspasmolytic action is manifestedin the smooth muscle of the stomach, the intestinal tract, theurogenital tract and the respiratory system. Finally, there is someevidence that the compounds influence the cholesterol level and lipidlevel of the blood. These effects complement one another and thecompounds are thus highly desirable as pharmaceutical agents to be usedin the treatment of hypertension and conditions characterized by aconstriction of the coronary blood vessels.

Pharmaceutical compositions for effecting such treatment will contain amajor or minor amount, e.g. from 95 to 0.5%, of at least one2,6-diamino-l,4- dihydropyridine as herein defined in combination with apharmaceutical carrier, the carrier comprising one or more solid,semi-solid or liquid diluent, filler and formulation adjuvant which isnon-toxic, inert and pharmaceutically acceptable. Such pharmaceuticalcompositions are preferably in dosage unit form; i.e. physicallydiscrete units containing a predetermined amount of the drugcorresponding to a fraction or multiple of the dose which is calculatedto produce the desired therapeutic response. The dosage units cancontain one, two, three, four or more single doses or, alternatively,one-half, third or fourth of a single dose. A single dose preferablycontains an amount sufficient to produce the desired therapeutic effectupon administration at one application of one or more dosage unitsaccording to a predetermined dosage regimen, usually a whole, half,third or quarter of the daily dosage administered once, twice, three orfour times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, generally the daily dose will befrom about 0.5 to about 1800 mg/kg,

preferably 2.5 to 900 mg/kg, when administered parenterally and fromabout 25 to about 4500 mg/kg, preferably to 1800 mg/kg, whenadministered orally. In some instances a sufficient therapeutic effectcan be obtained at lower doses while in others, larger doses will berequired.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solution, and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose,sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare' prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a non-toxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax. or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively a mea-. sured amount of the compound is placed in a vialand the vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

The following examples will serve to further typify the nature of thepresent invention through the presentation of specific embodiments.These examples should not be construed as a limitation on the scope ofthe invention since the subject matter regarded as the invention is setforth in the appended claims.

EXAMPLE 1 Upon boiling a solution of 5.3 g benzaldehyde and 13.0 gamidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours,2,6-diamino-4-pheny1-1,4- dihydropyridine-3,S-dicarboxylic acid diethylester of m.p. 139C (isopropanol) is obtained.

Yield: 59% of theory.

EXAMPLE 2 11502000 I I OOCzHs HaNl i NH2 Upon boiling a solution of 7.6g Z-nitrobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150ml ethanol for 2 hours, 2,6-diamino-4-(2-nitrophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester of m.p. 142C(ethanol) is obtained.

Yield: 56% of theory.

EXAMPLE 3 I-NOz Upon boiling a solution of 15.1 g 3- nitrobenzaldehydeand 26.0 g amidinoacetic acid ethyl ester in 250 m1 ethanol for 2 hours,2,6-diamino-4-(3- nitropheny1)- l ,4-dihydropyridine-3 ,S-dicarboxylicacid diethyl ester of m.p. 175 176C (ethanol) is obtained.

Yield: 63% of theory.

EXAMPLE4 H C2O0C I I CO0C2H5 H2NlN NH2 H Upon boiling a solution of 6.5g 3- cyanobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150ml ethanol for 2 hours, 2,6-diamino-4-(3-cyanopheny1)-1,4-dihydropyridine-3,5- dicarboxylic acid diethylester of m.p. 176C (isopropanol) is obtained.

Yield: 55% of theory.

EXAMPLE 5 CHa COOCzHs Upon boiling a solution of 6.0 g 2-methylbenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 mlethanol for 2 hours, 2,6-diamino- 4-( 2-methylphenyl )-l,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester of m.p. 158C(ethanol) is obtained.

methoxybenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in mlethanol for 2 hours, 2,6-diamino- 4-(2-methoxyphenyl)-1,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester of m.p. 147C(ethanol) is obtained.

Yield: 72% of theory.

EXAMPLE 7 Upon boiling a solution of 6.2 g 2- fluorobenzaldehyde and13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 1 hour,2,6-diamino-4- (2-fluorophenyl l ,4-dihydropyridine-3 ,S-dicarboxylicacid diethyl ester of m.p. l28130C (ethanol) is obtained.

Yield: 49% of theory.

EXAMPLE 8 Upon boiling a solution of 8.7 g Z-trifluoromethylbenzaldehydeand 13.0 g amidinoacetic acid ethyl ester in 150 ml of ethanol for 2hours, 2,6-diamino-4-(2- trifluoromethylphenyl )-1,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester of m.p. 191C(ethanol) is obtained.

Yield: 70% of theory.

EXAMPLE 9 EXAMPLE 10 H CH Upon boiling a solution of 5.0 g acetaldehydeand 26.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours,2,6-diamino4-methyl-l ,4- dihydropyridine-3,S-dicarboxylic acid diethylester of m.p. 136C (ethyl acetate/petroleum ether) is obtained.

Yield: 61% of theory.

EXAMPLE 1 l Upon boiling a solution of 9.3 g 3-nitro-6-chlorobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 mlethanol for 2 hours, 2,6-diamino- 4-( 3-nitro-6-chlorophenyl )-l,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester of m.p. C(ethanol) is obtained.

Yield: 48% of theory.

EXAMPLE 12 ON H mommy 00002115 HZNILN/NH:4 H

Upon heating a solution of 5.4 g a-pyridinaldehyde and 13.0 gamidinoacetic acid ethyl ester in ml eth anolfor 2 hours,2,6-diamino-4-(a-pyridyl)-1.4- dihydropyridine-3,S-dicarboxylic aciddiethyl ester of m.p. C (ethanol) is obtained. 1

Yield: 74% of theory.

EXAMPLE 13 omoMocm HaCzOOC COOCzHu HzN NH:

Upon heating a solution of 8.4 g 4,6- dimethoxypyrimidine-S-aldehyde and13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours,2,6- diamino-4-(4,6dimethoxypyrimid-5-yl)-1,4-

dihydropyridine-3,S-dicarboxylic acid diethyl ester of' mp. 219C(ethanol) is obtained.

Yield: 56% of theory.

EXAMPLE 14 IIClObC 00002115 nmkgl mn Upon boiling a solution of 4.8 gfuran-2-aldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 mlethanol for two hours, 2,6-diamino-4-(furyl-2)-1,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester of m.p. l47l48C(ethanol) is obtained.

Yield: 74% of theory.

EXAMPLE H5C2OOC I I COOCzHs HlzNlN Upon boiling a solution of 7.8 gl-naphthaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 mlethanol for 2 hours, 2,6-diamino-4-(naphth-l-yl)-l,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. l62-163C(ethanol) is obtained.

Yield: 52% of theory.

EXAMPLE 16 3 k mczoocl "430001115 H7NlN NH2 H Upon heating a solution of7.8 g quinoline-4- aldehyde and 13.0 g amidinoacetic acid ethyl ester in200 ml ethanol for 2 hours, 2,6-diamino-4-(quino1-4-y|)-l,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester of m.p. 145(ethanol) is obtained.

Yield: 58% of theory.

EXAMPLE l7 son,

EXAMPLE 18 Upon heating a solution of 9.1 g biphenyl-2-aldehyde and 13.0g amidinoacetic acid ethyl ester in 200 ml ethanol for 2 hours,2,6-diamino-4-(biphenyl-2-yl)-1,4- dihydropyridine-3,S-dicarboxylic aciddiethyl ester of m.p. 215 (ethanol) is obtained.

Yield: 33% of theory.

EXAMPLE l9 HCEC-CHzO O C C0 OCHqCECH Upon heating a solution of 7.6 gnitrobenzaldehydc and 14.0 g amidinoacetic acid propargyl ester in 200ml ethanol for 2 hours, 2,6-diamino-4-(3-nitrophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid dipropargyl ester of m.p.(ethanol) is obtained.

Yield: 59% of theory.

EXAMPLE 20 C O O CH(CHJ)2 Upon heating a solution of 5.4 gpyridine-4-aldehyde and 14,4 g amidinoacetic acid isopropyl ester in 200ml ethanol, 2,6-diamino-4-(pyrid-4-yl )-l ,4-dihydropyridine-3,S-dicarboxylic acid diisopropyl ester of m.p. 263C(ethanol) is obtained.

Yield: 76% of theory.

EXAMPLE 21 HC2OOC-U H-CO O CH(CH3)2 H2N N -N1Iz H Upon heating asolution of 10.1 g benzylidenecyanoacetic acid ethyl ester, 7,2 gamidinoacetic acid isopropyl ester and 0.6 g sodium ethylate in 150 mlethanol for four hours, 2,6-diamino-4-phenyl-1,4-dihydropyridine-3,S-dicarboxylic acid 3-ethyl ester 5-isopropylester of m.p. 170 is obtained.

Yield: 54% of theory.

EXAMPLE 22 EXAMPLE 23 Upon heating a solution of 7.3 g 2-azidobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 mlethanol for 2 hours, 2,6-diamino-4-(2azidophenyl)-1,4dihydropyridine-3,S-dicarboxylic acid diethyl ester ofm.p. 250C (ethanol) is obtained.

Yield: 46% of theory.

EXAMPLE 24 l-COO C2115 CO 0 C2115 Upon boiling a solution of 8.9 g3-carbethoxybenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in100 ml ethanol for 2 hours, 2,6-diamino-4-(3- carbethoxypheny1)-l,4-dihydropyridine-3,5-

dicarboxylic acid diethyl ester of m.p. 191C (ethanol) is obtained.

Yield: 32% of theory. What is claimed is: l. A compound of the formulawherein R is hydrogen; lower alkyl; alkenyl of 2 to 4 carbon atoms;alkynyl of 2 to 4, carbon atoms phenyl; substituted phenyl in which thesubstituents are one to three members selected from the group consistingof lower alkyl, lower alkoxy, halogeno, nitro, cyano, trifluoromethyl,azido, carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl,lower alkylthio or phenyl; or naphthyl; and

each of R and R taken independentlyof the other,

is, lower alkoxy, lower alkoxy)lower alkoxy), alkenyloxy of 2 to 4carbon atoms, alkynyloxy of 2 to 4 carbon atoms, amino, lower alkylaminoor di(- lower alkyl)amino.

2. A compound according to claim 1 wherein R and R are lower alkoxy.

3. a compound according to claim 2 wherein R is lower alkyl, naphthyl,phenyl or phenyl substituted with from one to three substituentsselected from the group consisting of lower alkyl, lower alkoxy,halogeno, nitro,

. cyano, trifluoromethyl, azido, carbo(lower alkoxy),

lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio or phenyl.

4. The compound according to claim 1 which is 2,6-diamino-4-phenyl-1,4-dihydropyridine-3 ,5 dicarboxylic acid diethylester.

5. The compound according to claim 1 which is 2,6- diamino-4-(2-nitrophenyl )-l ,4-dihydropyridine-3,5- dicarboxylic acid diethylester.

6. The compound according to claim 1 which is 2,6-diamino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5- dicarboxylic aciddiethyl ester.

'7. The compound according to claim 1 which is 2,6- diamino4-(3-cyanophenyl 1 ,4-dihydropyridine-3 ,5- dicarboxylic acid diethylester.

8. The compound according to claim 1 which is 2,6- diamino-4-(Z-methylphenyl )-1 ,4-dihydropyridine-3 ,5- dicarboxylic acid diethylester.

9. The compound according to claim 1 which is 2,6- diamino-4-(2-methoxyphenyl l ,4-dihydropyridine- 3,5-dicarboxylic acid diethylester.

10. A compound according to claim 1 which is 2,6-diamino-4-(2-fluorophenyl)-1,4-dihydropyridine3 ,5 dicarboxylic aciddiethyl ester.

11. A compound according to claim 1 which is 2,6- diamino-4-(2-trifluoromethylphenyl )-l ,4- dihydropyridine-3,S-dicarboxylic aciddiethyl ester.

12. A compound according to claim 1 which is 2,6- diamino-4-(3-trifluoromethylphenyl )-1 ,4- dihydropyridine-3,S-dicarboxylic aciddiethyl ester.

13. A compound according to claim 1 which is 2,6- diamino-4-methyl- 1,4-dihydropyridine-3 ,5- dicarboxylic acid diethyl ester.

dicarboxylic acid dipropargyl ester.

19. A compound according to claim 1 which is 2,6- diamino-4-phenyll,4-dihydropyridine-3 ,5- dicarboxylic acid 3-ethyl ester 5-isopropylester.

20. A compound according to claim 1 which is 2,6- diamino-4-(Z-nitrophenyl l ,4-dihydropyridine3 ,5- dicarboxylic acid-3-isopropylester S-ethyl ester.

21. A compound according to claim 1 which is 2,6- diamino-4-(2-azidophenyl l ,4-dihydropyridine-3 ,5- dicarboxylic acid diethylester.

22. A compound according to claim 1 which is 2,6- diamino-4-(3-carbethoxyphenyl l ,4 dihydropyridine- 3,5-dicarboxylic acid diethylester. =k 1

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 whereinR1 and R2 are lower alkoxy.
 3. a compound according to claim 2 wherein Ris lower alkyl, naphthyl, phenyl or phenyl substituted with from one tothree substituents selected from the group consisting of lower alkyl,lower alkoxy, halogeno, nitro, cyano, trifluoromethyl, azido,carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl, loweralkylthio or phenyl.
 4. The compound according to claim 1 which is2,6-diamino-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethylester.
 5. The compound according to claim 1 which is2,6-diamino-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 6. The compound according to claim 1 which is2,6-diamino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 7. The compound accOrding to claim 1 which is2,6-diamino-4-(3-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 8. The compound according to claim 1 which is2,6-diamino-4-(2-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 9. The compound according to claim 1 which is2,6-diamino-4-(2-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 10. A compound according to claim 1 which is2,6-diamino-4-(2-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 11. A compound according to claim 1 which is2,6-diamino-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 12. A compound according to claim 1 which is2,6-diamino-4-(3-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 13. A compound according to claim 1 which is2,6-diamino-4-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethylester.
 14. A compound according to claim 1 which is2,6-diamino-4-(3-nitro-6-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 15. A compound according to claim 1 which is2,6-diamino-4-(naphth-1-yl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 16. A compound according to claim 1 which is2,6-diamino-4-(4-methylmercaptophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 17. A compound according to claim 1 which is2,6-diamino-4-(biphenyl-2-yl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 18. A compound according to claim 1 which is2,6-diamino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddipropargyl ester.
 19. A compound according to claim 1 which is2,6-diamino-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethylester 5-isopropyl ester.
 20. A compound according to claim 1 which is2,6-diamino-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid-3-isopropyl ester 5-ethyl ester.
 21. A compound according to claim1 which is2,6-diamino-4-(2-azidophenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 22. A compound according to claim 1 which is2,6-diamino-4-(3-carbethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester.